Lung fibrosis modeling and compound testing platform using fibrotic lung ECM that recreates the fibrotic disease environment to improve predictiveness and accelerate anti-fibrotic drug development

使用纤维化肺 ECM 的肺纤维化建模和复合测试平台，可重建纤维化疾病环境，以提高预测性并加速抗纤维化药物的开发

• 批准号: 10793211
• 负责人: John David O'Neill
• 金额: $ 10.93万
• 依托单位: XYLYX BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10793211
• 关键词: 3-Dimensional; Acceleration; Animal Model; Animals; Basic Science; Biocompatible Materials; Biological Assay; Biology; Biomanufacturing; Biomechanics; Biotechnology; Cell Culture Techniques; Cells; Chronic lung disease; Coenzyme A; Collagen; Collagen Type I; Data Set; Decision Making; Dependence; Development; Diagnosis; Disease; Disease Progression; Disease model; Documentation; Drug Modelings; Drug Screening; Environment; Etiology; Experimental Models; Extracellular Matrix; FDA approved; Facility Controls; Fibroblasts; Gel; Gene Expression; Genes; Goals; Human; Hydrogels; In Vitro; International; Interstitial Lung Diseases; Intervention; Interview; Investigation; Knowledge; Legal patent; Life; Lung; Lung Transplantation; Lung diseases; Manuscripts; Marketing; Mechanics; Methods; Modeling; Multiomic Data; Organ Donor; Output; Paper; Pathogenesis; Patient-Focused Outcomes; Performance; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenotype; Physiological; Pirfenidone; Polystyrenes; Predictive Value; Process; Protein Secretion; Protocols documentation; Publications; Publishing; Pulmonary Fibrosis; Pulmonary alveolar structure; Quality Control; Reporting; Reproducibility; Research; Respiratory physiology; Risk Reduction; Sampling; Scientist; Small Business Innovation Research Grant; Specific qualifier value; Specificity; Standardization; Structure of parenchyma of lung; Technology; Test Result; Testing; Time; Tissue Model; Tissues; Validation; Work; commercialization; comparative; cost; drug development; drug discovery; drug testing; empowerment; fibrotic lung; high risk; human tissue; idiopathic pulmonary fibrosis; improved; in vitro Model; in vitro testing; in vivo; manufacture; manufacturing process; metabolomics; mortality; nintedanib; novel; novel therapeutics; predictive modeling; product development; quality assurance; research and development; scale up; standard of care; stem; success; supply chain; technological innovation; therapeutic development; transcriptome sequencing; transcriptomics; validation studies; verification and validation

PROJECT ABSTRACT Xylyx is developing a pulmonary fibrosis disease modeling and anti-fibrotic compound testing platform aimed at improving the physiological relevance and predictive value of in-vitro models for idiopathic pulmonary fibrosis (IPF) to power the investigation of IPF disease biology and accelerate development of drugs to treat IPF. Devastating, intractable, and life-threatening, IPF is an interstitial lung disease characterized by obliteration of pulmonary alveoli and progressive loss of respiratory function. Over 55,000 new cases of IPF are diagnosed each year. Median survival is 3–4 years, and annual mortality in the US exceeds 40,000. The etiology and pathogenesis of IPF remain unknown. Predictive animal and in-vitro models of IPF for basic science research and drug development are severely lacking, leaving a significant unmet need and market opportunity for a physiologically-relevant in-vitro platform that enables high-fidelity cell-based phenotypic studies of IPF. This SBIR Fast Track will support development and validation studies for commercialization of an IPF disease modeling and compound testing platform that recapitulates in vitro key features of the human IPF disease environment and has been shown to support fibrotic phenotype of human lung fibroblasts to improve cell-based assays in early-stage anti-fibrotic drug discovery. The technological innovation is the product’s human IPF fibrotic lung specificity stemming from proprietary methods for isolating acellular human IPF lung extracellular matrix (ECM) with the composition and biomechanics of human IPF lung tissue. Our ‘physiomimetic approach’ yields standardized human fibrotic lung cell culture substrates for predictive in-vitro models of IPF that enable more physiologic and thus more predictive studies, providing a major competitive advantage over existing products like collagen-coated polystyrene plates. The goal is validation and commercialization of standard human IPF lung ECM disease modeling and compound testing platform for predictive in-vitro models of IPF to greatly reduce dependence on animal models and enable more relevant results for IPF drug developers. Specific aims are to: (i) determine transcriptomic and metabolomic profiles of lung fibroblasts in human IPF and normal lung ECM hydrogels, (ii) evaluate quality and consistency of human IPF and normal lung ECM hydrogels, (iii) perform compound testing studies with IPF standard-of-care drugs. After successful completion of the Fast Track project, Xylyx will commercialize the IPF compound testing platform to scientists in pharmaceutical companies in need of predictive IPF disease models for drug discovery and screening, thus reducing the significant costs associated with late-stage attrition due to poor efficacy, and facilitating the development of improved treatment options for the more than 3 million sufferers of IPF worldwide. The product of this SBIR Fast Track will immediately enter the rapidly growing cell culture market segment in biopharma and drug development, valued at USD $6.4B in 2014 and estimated to reach USD $29.2B by 2024, and will support drug development aimed at the USD $3.0B IPF treatment market.

项目摘要